Gut associated lymphoid tissue (GALT) is depleted of most CD4 cells early after HIV infection and does not reconstitute with antiretroviral therapy (ARV), yet few clinical problems are reported in this population with altered gut immunity. Importantly, recent studies have documented increasing rectal neoplasia from the chronic, latent mucosal pathogen human papilloma virus (HPV). In our preliminary data we document the massive depletion of CD4+ T cells from lamina propria (LP) and show that effector cells populating the LP do not recover with ARV. However, we do show the central memory (CM) population of GALT has potential for reconstitution with ARV. In addition we have found the frequency of HIV DNA+ cells in GALT continues to increase after ARV initiation and in Projects 1 and 2 we document frequent detection of HIV episomes. These observations suggest a model of ongoing cryptic replication of HIV in GALT of ARV treated individuals that leads to a gradual depletion of the CM population, which, in turn, eventually manifests as clinical disease. This model is in agreement with recent observations in SIV infected non-human primates where the size of the CM population predicted disease progression and survival. We therefore hypothesize that cryptic HIV replication and the subsequent depletion of CD4 cells undermines immune function in gut associated lymphoid tissue (GALT). To investigate this hypothesis we will study the degree to which cryptic replication of HIV in GALT determines the natural history of two common, chronic, latent mucosal infections with frequent rectal reactivation (i.e., herpes simplex type 2 [HSV2] and cytomegalovirus [CMV]). We will measure the frequency of HIV episomes in CD4 subsets (especially the CM subset) in GALT, LN, and PB, the frequency of HSV2 and CMV specific CD4 and CDS T cells in each compartment, and the frequency of rectal reactivation of HSV2 and CMV. We will determine the relationship between the frequency of cryptic HIV replication to the size of the CM in PP and effector memory (EM) population in LP and the ability of the immune system to control reactivation of HSV2 and CMV. We believe completion of these studies will provide a more complete understanding of HIV pathogenesis which will translate into targeted therapies to improve GALT immune function.